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Objective biomarkers of food intake are a sought-after goal in nutrition research. Most biomarker development to date has focused on metabolites detected in blood, urine, skin, or hair, but detection of consumed foods in stool has also been shown to be possible via DNA sequencing. An additional food macromolecule in stool that harbors sequence information is protein. However, the use of protein as an intake biomarker has only been explored to a very limited extent. Here, we evaluate and compare measurement of residual food-derived DNA and protein in stool as potential biomarkers of intake. We performed a pilot study of DNA sequencing-based metabarcoding and mass spectrometry-based metaproteomics in five individuals' stool sampled in short, longitudinal bursts accompanied by detailed diet records ( n = 27 total samples). Dietary data provided by stool DNA, stool protein, and written diet record independently identified a strong within-person dietary signature, identified similar food taxa, and had significantly similar global structure in two of the three pairwise comparisons between measurement techniques (DNA-to-protein and DNA-to-diet record). Metaproteomics identified proteins including myosin, ovalbumin, and beta-lactoglobulin that differentiated food tissue types like beef from dairy and chicken from egg, distinctions that were not possible by DNA alone. Overall, our results lay the groundwork for development of targeted metaproteomic assays for dietary assessment and demonstrate that diverse molecular components of food can be leveraged to study food intake using stool samples.

Background: Given the increasing interest in dietary interventions to improve cardiovascular health, this trial assessed the impact of fortified eggs (FE) versus nonegg supplemented diet and time-restricted eating (TRE) versus usual care diet on cardiovascular biomarkers., Methods: The study was a unblinded, 2-by-2 factorial design, which randomized patients, with either a prior cardiovascular event or 2 cardiovascular risk factors, to FE or a nonegg supplemented diet and TRE or usual care diet. Patients randomized to FE were instructed to consume at least 12 FE/week (with eggs provided); those on a nonegg supplemented diet restricted egg consumption to <2 eggs/week. TRE participants were instructed to consume all calories within an 8-hour window daily and fasted for the remaining 16 hours. Patients randomized to usual diet were advised to maintain current dietary habits. Follow-up was performed in-person at 1 and 4 months, and telephone calls at 2 and 3 months. Co-primary endpoints were 4-month LDL- and HDL-cholesterol. Secondary endpoints included additional lipids, cardiometabolic- and inflammatory biomarkers and micronutrient levels at 4-months., Results: Overall, 140 patients were randomized with median (25th, 75th percentiles) age 66 (58, 73) years; 72 (51%) women, 38 (27%) Black, and 33 (24%) with diabetes mellitus. The difference in least squares (LS) means from baseline to 4-months for HDL and LDL levels revealed no significant clinical difference between FE vs nonegg supplemented diet (HDL: -0.64 mg/dL [95% CI: -3.86, 2.58]; LDL: -3.14 mg/dL [-10.81, 4.52]) and TRE vs usual care diet (HDL: 1.51 mg/dL [-1.65, 4.68]; LDL 1.17 mg/dL [-6.36, 8.70]). Prespecified subgroups revealed a nonsignificant HDL increase and LDL decrease with FE in patients ≥65 years., Conclusions: These data did not demonstrate clinically relevant differences in changes in LDL and HDL levels over 4 months with FE and TRE compared with nonegg supplemented diet and usual care diet, respectively, providing evidence that adverse short-term lipid and biomarker changes did not occur with FE consumption., Trial Registration: ClinicalTrials.gov Identifier: NCT04673721., Competing Interests: Declaration of competing interest NN received speaker fees from AstraZeneca and Bayer. RJM received research support from Eggland's Best to his institution to support the trial. NJP received research support from Alnylam, Amgen, Bayer, Boehringer Ingelheim, Eggland's Best, Eli Lilly, Novartis, Novo Nordisk, Merck. Consultation/Advisory Panels for Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Esperion, AstraZeneca, Merck, Novartis, and Novo Nordisk. Executive Committee member for trials sponsored by Novo Nordisk and by Amgen. DSMB for trials sponsored by J+J and Novartis. Medical advisory board for Miga Health. DH, KM, BTS and MW are employees of Eggland's Best, LLC, Malvern, PA, USA. JH has no disclosures., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Existing behavioral weight management interventions produce clinically meaningful weight loss. The onset of the COVID-19 pandemic led to the quick transition of such interventions from in-person to virtual platforms. This provided a unique opportunity to compare engagement and outcomes for an in-person versus virtually delivered weight management intervention., Methods: A non-randomized comparison of engagement and weight outcomes was performed between two cohorts who participated in a weight management intervention in person ( N  = 97) versus three who participated virtually via videoconference ( N  = 134). Various metrics of engagement were examined, including group class and individual phone call attendance and duration, and retention for weight assessments. Behavioral targets of daily caloric intake and step-counts and the clinical weight outcome were explored., Results: Cohorts (mean [standard deviation] age 47.3 (11.5), 67.1% women: 86.8% White) that participated virtually attended more group sessions ( p  < 0.001) and had maintenance telephone calls that were of a longer duration ( p  < 0.001). No other engagement or weight outcomes significantly differed by delivery modality., Conclusions: Virtual weight management programs are promising and may generate similar outcomes to those delivered in-person. Future research should seek to understand how best to promote and sustain engagement in virtual interventions., Competing Interests: Samantha Pabich is a Consultant for Eli Lilly and Company, and a Consultant for Dynamed. Ryan Shaw is a Consultant for Cerner Enviza. No other authors declare any interests., (© 2024 The Author(s). Obesity Science & Practice published by John Wiley & Sons Ltd and World Obesity and The Obesity Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Partner support is associated with better weight loss outcomes in observational studies, but randomized trials show mixed results for including partners. Unclear is whether teaching communication skills to couples will improve weight loss in a person attempting weight loss (index participant)., Purpose: To compare the efficacy of a partner-assisted intervention versus participant-only weight management program on 24-month weight loss., Methods: This community-based study took place in Madison, WI. Index participants were eligible if they met obesity guideline criteria to receive weight loss counseling, were aged 18-74 years, lived with a partner, and had no medical contraindications to weight loss; partners were aged 18-74 years and not underweight. Couples were randomized 1:1 to a partner-assisted or participant-only intervention. Index participants in both arms received an evidence-based weight management program. In the partner-assisted arm, partners attended half of the intervention sessions, and couples were trained in communication skills. The primary outcome was index participant weight at 24 months, assessed by masked personnel; secondary outcomes were 24-month self-reported caloric intake and average daily steps assessed by an activity tracker. General linear mixed models were used to compare group differences in these outcomes following intent-to-treat principles., Results: Among couples assigned to partner-assisted (n = 115) or participant-only intervention (n = 116), most index participants identified as female (67%) and non-Hispanic White (87%). Average baseline age was 47.27 years (SD 11.51 years) and weight was 106.55 kg (SD 19.41 kg). The estimated mean 24-month weight loss was similar in the partner-assisted (2.66 kg) and participant-only arms (2.89 kg) (estimated mean difference, 0.23 kg [95% CI, -1.58, 2.04 kg], p=0.80). There were no differences in 24-month average daily caloric intake (estimated mean difference 50 cal [95% CI: -233, 132 cal], p=0.59) or steps (estimated mean difference 806 steps [95% CI: -1675, 64 steps], p=0.07). The percentage of participants reporting an adverse event with at least possible attribution to the intervention did not differ by arm (partner-assisted: 9%, participant-only, 3%, p = 0.11)., Conclusions: Partner-assisted and individual weight management interventions led to similar outcomes in index participants., Trial Registration: Clinicaltrials.gov NCT03801174, January 11, 2019., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective biomarkers of food intake are a sought-after goal in nutrition research. Most biomarker development to date has focused on metabolites detected in blood, urine, skin or hair, but detection of consumed foods in stool has also been shown to be possible via DNA sequencing. An additional food macromolecule in stool that harbors sequence information is protein. However, the use of protein as an intake biomarker has only been explored to a very limited extent. Here, we evaluate and compare measurement of residual food-derived DNA and protein in stool as potential biomarkers of intake. We performed a pilot study of DNA sequencing-based metabarcoding (FoodSeq) and mass spectrometry-based metaproteomics in five individuals' stool sampled in short, longitudinal bursts accompanied by detailed diet records ( n =27 total samples). Dietary data provided by stool DNA, stool protein, and written diet record independently identified a strong within-person dietary signature, identified similar food taxa, and had significantly similar global structure in two of the three pairwise comparisons between measurement techniques (DNA-to-protein and DNA-to-diet record). Metaproteomics identified proteins including myosin, ovalbumin, and beta-lactoglobulin that differentiated food tissue types like beef from dairy and chicken from egg, distinctions that were not possible by DNA alone. Overall, our results lay the groundwork for development of targeted metaproteomic assays for dietary assessment and demonstrate that diverse molecular components of food can be leveraged to study food intake using stool samples.

There is a substantial body of clinical evidence supporting the beneficial effects of lower-carbohydrate dietary patterns on multiple established risk factors associated with insulin resistance and cardiovascular diseases in adult populations. Nutrition and health researchers, clinical practitioners, and stakeholders gathered for, "The Scientific Forum on Nutrition, Wellness, and Lower-Carbohydrate Diets: An Evidence- and Equity-Based Approach to Dietary Guidance" to discuss the evidence base around lower-carbohydrate diets, health outcomes, and dietary guidance. Consensus statements were agreed upon to identify current areas of scientific agreement and spotlight gaps in research, education, and practice to help define and prioritize future pathways. Given the evidence base and considering that most American adults are living with at least one nutrition-related chronic disease, there was consensus that including a lower-carbohydrate dietary pattern as one part of the Dietary Guidelines for Americans could help promote health equity among the general population., Competing Interests: JV has stock options in Virta Health and receives royalties for books on low-carbohydrate diets, and serves as a scientific advisor for SIMPLY GOOD FOODS. BG is a scientific consultant on continuous ketone monitor development for Abbott Laboratories (2020 – present) and serves on the Cook-Keto scientific advisory board (2023). SP is an advisor to, and has equity in, Virta Health. JSl has received research funds in the last 5 years from USDA, NIH, Taiyo, Barilla, and the Institute on the Environment. She serves on the Scientific Advisory Board for SIMPLY GOOD FOODS, the Sustainable Nutrition Scientific Board, and the Quality Carbohydrate Coalition. She owns and manages the Slavin Sisters Farm LLC, a 119 acre mixed-use family farm in Walworth, WI. AK has consulted for SIMPLY GOOD FOODS. MH authored, “The Dietitian’s Dilemma” and receives royalties for the book. JV, WY, BG, SP, MH, and JSp received an honorarium for presenting at the Scientific Forum on Nutrition, Wellness, and Lower-Carbohydrate Diets: An Evidence and Equity-Based Approach to Dietary Guidance. MC and FH have no COI to report., (Copyright © 2024 Volek, Yancy, Gower, Phinney, Slavin, Koutnik, Hurn, Spinner, Cucuzzella and Hecht.)

Background: Weight loss is commonly recommended before total knee arthroplasty (TKA) despite inconsistent evidence for better outcomes. This study sought to examine the impacts of preoperative weight loss on patient-reported and adverse outcomes among TKA patients supervised by a medical weight management clinic., Methods: This study retrospectively analyzed patients who underwent medical weight management supervision within 18 months before TKA comparing patients who did and did not have clinically relevant weight loss. Preoperative body mass indices, demographics, Patient-Reported Outcomes Measurement Information System physical function and pain interference scores, pain intensity scores, and adverse outcomes were extracted. Multivariable linear regressions were performed to determine if preoperative weight loss correlated with patient-reported outcomes after controlling for confounders., Results: There were 90 patients, 75.6% women, who had a mean age of 65 years (range, 42-82) and were analyzed. There were 51 (56.7%) patients who underwent clinically relevant weight loss with a mean weight loss of 10.4% and experienced no difference in adverse outcomes. Preoperative weight loss predicted significantly improved 3-month postoperative physical function (β = 15.2 [13.0-17.3], P < .001), but not pain interference (β = -18.9 [-57.1-19.4], P = .215) or pain intensity (β = -1.8 [-4.9-1.2], P = .222) scores., Conclusion: We found that medically supervised preoperative weight loss predicted improvement in physical function 3 months after TKA. This weight loss caused no major adverse effects. Further research is needed to understand the causal relationships between preoperative weight loss, medical supervision, and outcome after TKA and to elucidate potential longer-term benefits in a larger sample., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: High body mass index (BMI) is associated with adverse outcomes after total knee arthroplasty (TKA). Thus, many patients are advised to lose weight before TKA. This study examined how weight loss before TKA is associated with adverse outcomes depending on patients' initial BMI., Methods: This was a retrospective study of 2,110 primary TKAs at a single academic center. Data on preoperative BMIs, demographics, comorbidities, and incidences of revision or prosthetic joint infection (PJI) were obtained. Multivariable logistic regressions segmented by patients' initial (1-year preoperative) BMI classifications were performed to determine if a > 5% BMI decrease from 1 year or 6 months preoperatively predicted PJI and revision controlling for patient age, race, sex, and Elixhauser comorbidity index., Results: Preoperative weight loss did not predict adverse outcomes for patients who had Obesity Class II or III. 6-month weight loss had greater odds of adverse outcomes than 1-year weight loss and most significantly predicted the occurrence of 1-year PJI (adjusted odds ratio: 6.55, P < .001) for patients who had Obesity Class 1 or lower., Conclusion: This study does not show a statistically significant effect to patients who had Obesity Class II and III losing weight preoperatively with respect to PJI or revision. For patients who have Obesity Class I or lower pursuing TKA, future research should consider potential risks associated with weight loss. Further study is needed to determine if weight loss can be implemented as a safe and effective risk reduction strategy for specific BMI classes of TKA patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In response to the escalating global obesity crisis and its associated health and financial burdens, this paper presents a novel methodology for analyzing longitudinal weight loss data and assessing the effectiveness of financial incentives. Drawing from the Keep It Off trial-a three-arm randomized controlled study with 189 participants-we examined the potential impact of financial incentives on weight loss maintenance. Given that some participants choose not to weigh themselves because of small weight change or weight gains, which is a common phenomenon in many weight-loss studies, traditional methods, for example, the Generalized Estimating Equations (GEE) method tends to overestimate the effect size due to the assumption that data are missing completely at random. To address this challenge, we proposed a framework which can identify evidence of missing not at random and conduct bias correction using the estimating equation derived from pairwise composite likelihood. By analyzing the Keep It Off data, we found that the data in this trial are most likely characterized by non-random missingness. Notably, we also found that the enrollment time (i.e., duration time) would be positively associated with the weight loss maintenance after adjusting for the baseline participant characteristics (e.g., age, sex). Moreover, the lottery-based intervention was found to be more effective in weight loss maintenance compared with the direct payment intervention, though the difference was non-statistically significant. This framework's significance extends beyond weight loss research, offering a semi-parametric approach to assess missing data mechanisms and robustly explore associations between exposures (e.g., financial incentives) and key outcomes (e.g., weight loss maintenance). In essence, the proposed methodology provides a powerful toolkit for analyzing real-world longitudinal data, particularly in scenarios with data missing not at random, enriching comprehension of intricate dataset dynamics., (© 2023. The Author(s).)

Eating a varied diet is a central tenet of good nutrition. Here, we develop a molecular tool to quantify human dietary plant diversity by applying DNA metabarcoding with the chloroplast trnL -P6 marker to 1,029 fecal samples from 324 participants across two interventional feeding studies and three observational cohorts. The number of plant taxa per sample (plant metabarcoding richness or pMR) correlated with recorded intakes in interventional diets and with indices calculated from a food frequency questionnaire in typical diets (ρ = 0.40 to 0.63). In adolescents unable to collect validated dietary survey data, trnL metabarcoding detected 111 plant taxa, with 86 consumed by more than one individual and four (wheat, chocolate, corn, and potato family) consumed by >70% of individuals. Adolescent pMR was associated with age and household income, replicating prior epidemiologic findings. Overall, trnL metabarcoding promises an objective and accurate measure of the number and types of plants consumed that is applicable to diverse human populations.

Introduction: Obtaining body weights remotely could improve feasibility of pragmatic trials. This investigation examined whether weights collected via cellular scale or electronic health record (EHR) correspond to gold standard in-person study weights., Methods: The agreement of paired weight measurements from cellular scales were compared to study scales from a weight loss intervention and EHR-collected weights were compared to study scales from a weight loss maintenance intervention. Differential weight change estimates between intervention and control groups using both pragmatic methods were compared to study collected weight. In the Log2Lose feasibility weight loss trial, in-person weights were collected bi-weekly and compared to weights collected via cellular scales throughout the study period. In the MAINTAIN weight loss maintenance trial, in-person weights were collected at baseline, 14, 26, 42 and 56 weeks. All available weights from the EHR during the study period were obtained., Results: On average, in Log2Lose cellular scale weights were 0.6 kg (95% CI: -2.9, 2.2) lower than in-person weights; in MAINTAIN, EHR weights were 2.8 kg (SE: -0.5, 6.0) higher than in-person weights. Estimated weight change using pragmatic methods and study scales in both studies were in the same direction and of similar magnitude., Conclusion: Both methods can be used as cost-effective and real-world surrogates within a tolerable variability for the gold-standard., Trial Registration: NCT02691260; NCT01357551., Competing Interests: We have no conflict of interest to disclose., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: The Center for Disease Control and Prevention's National Diabetes Prevention Program (NDPP) aims to help individuals with prediabetes avoid progression to type 2 diabetes mellitus (T2DM) through weight loss. Specifically, the NDPP teaches individuals to follow a low-fat, calorie-restricted diet and to engage in regular physical activity to achieve ≥ 5% body weight loss. Most NDPP participants, however, do not achieve this weight loss goal, and glycemic control remains largely unchanged. One promising opportunity to augment the NDPP's weight loss and glycemic effectiveness may be to teach participants to follow a very low-carbohydrate diet (VLCD), which can directly reduce post-prandial glycemia and facilitate weight loss by reducing circulating insulin and enabling lipolysis. To date, there have been no high-quality, randomized controlled trials to test whether a VLCD can prevent progression to T2DM among individuals with prediabetes. The aim of this study is to test the effectiveness of a VLCD version the NDPP (VLC-NDPP) versus the standard NDPP. We hypothesize the VLC-NDPP will demonstrate greater improvements in weight loss and glycemic control., Methods: We propose to conduct a 12-month, 1:1, randomized controlled trial that will assign 300 adults with overweight or obesity and prediabetes to either the NDPP or VLC-NDPP. The primary outcome will be glycemic control as measured by change in hemoglobin A1c (HbA1c) from baseline to 12 months. Secondary outcomes will include percent body weight change and changes in glycemic variability, inflammatory markers, lipids, and interim HbA1c. We will evaluate progression to T2DM and initiation of anti-hyperglycemic agents. We will conduct qualitative interviews among a purposive sample of participants to explore barriers to and facilitators of dietary adherence. The principal quantitative analysis will be intent-to-treat using hierarchical linear mixed effects models to assess differences over time., Discussion: The NDPP is the dominant public health strategy for T2DM prevention. Changing the program's dietary advice to include a carbohydrate-restricted eating pattern as an alternative option may enhance the program's effectiveness. If the VLC-NDPP shows promise, this trial would be a precursor to a multi-site trial with incident T2DM as the primary outcome., Trial Registration: NCT05235425. Registered February 11, 2022., (© 2022. The Author(s).)

Background: The use of digital technologies and software allows for new opportunities to communicate and engage with research participants over time. When software is coupled with automation, we can engage with research participants in a reliable and affordable manner. Research Electronic Data Capture (REDCap), a browser-based software, has the capability to send automated text messages. This feature can be used to automate delivery of tailored intervention content to research participants in interventions, offering the potential to reduce costs and improve accessibility and scalability., Objective: This study aimed to describe the development and use of 2 REDCap databases to deliver automated intervention content and communication to index participants and their partners (dyads) in a 2-arm, 24-month weight management trial, Partner2Lose., Methods: Partner2Lose randomized individuals with overweight or obesity and cohabitating with a partner to a weight management intervention alone or with their partner. Two databases were developed to correspond to 2 study phases: one for weight loss initiation and one for weight loss maintenance and reminders. The weight loss initiation database was programmed to send participants (in both arms) and their partners (partner-assisted arm) tailored text messages during months 1-6 of the intervention to reinforce class content and support goal achievement. The weight maintenance and reminder database was programmed to send maintenance-related text messages to each participant (both arms) and their partners (partner-assisted arm) during months 7-18. It was also programmed to send text messages to all participants and partners over the course of the 24-month trial to remind them of group classes, dietary recall and physical activity tracking for assessments, and measurement visits. All text messages were delivered via Twilio and were unidirectional., Results: Five cohorts, comprising 231 couples, were consented and randomized in the Partner2Lose trial. The databases will send 53,518 automated, tailored text messages during the trial, significantly reducing the need for staff to send and manage intervention content over 24 months. The cost of text messaging will be approximately US $450. Thus far, there is a 0.004% known error rate in text message delivery., Conclusions: Our trial automated the delivery of tailored intervention content and communication using REDCap. The approach described provides a framework that can be used in future behavioral health interventions to create an accessible, reliable, and affordable method for intervention delivery and engagement that requires minimal trial-specific resources and personnel time., Trial Registration: ClinicalTrials.gov NCT03801174; https://clinicaltrials.gov/ct2/show/NCT03801174?term=NCT03801174., (©Hailey N Miller, Corrine I Voils, Kate A Cronin, Elizabeth Jeanes, Jeffrey Hawley, Laura S Porter, Rachel R Adler, Whitney Sharp, Samantha Pabich, Kara L Gavin, Megan A Lewis, Heather M Johnson, William S Yancy Jr, Kristen E Gray, Ryan J Shaw. Originally published in JMIR Formative Research (https://formative.jmir.org), 06.09.2022.)

The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity., (© 2022. The Author(s).)

Objectives: To evaluate differences in factors associated with self-reported medication non-adherence to insulin and non-insulin medications in patients with uncontrolled type 2 diabetes., Methods: In this secondary analysis of a randomized trial in patients with obesity and uncontrolled type 2 diabetes, multivariable logistic regression was used to evaluate associations between several clinical factors (measured with survey questionnaires at study baseline) and self-reported non-adherence to insulin and non-insulin medications., Results: Among 263 patients, reported non-adherence was 62% (52% for insulin, 55% for non-insulin medications). Reported non-adherence to non-insulin medications was less likely in white versus non-white patients (odds ratio (OR) = 0.42; 95%CI: 0.22,0.80) and with each additional medication taken (OR = 0.75; 95%CI: 0.61,0.93). Non-adherence to non-insulin medications was more likely with each point increase in a measure of diabetes medication intensity (OR = 1.43; 95%CI: 1.01,2.03), the Problem Areas in Diabetes (PAID) score (OR = 1.06; 95%CI: 1.02,1.12), and in men versus women (OR = 3.03; 95%CI: 1.06,8.65). For insulin, reporting non-adherence was more likely (OR = 1.02; 95%CI: 1.00,1.04) with each point increase in the PAID., Discussion: Despite similar overall rates of reported non-adherence to insulin and non-insulin medications, factors associated with reported non-adherence to each medication type differed. These findings may help tailor approaches to supporting adherence in patients using different types of diabetes medications.

Evidence suggests that low carbohydrate (<130 g/day of carbohydrate) (LCD) and very low carbohydrate, ketogenic diets (typically <50 g/day of carbohydrate) (VLCKD) can be effective tools for managing diabetes given their beneficial effects on weight loss and glycemic control. VLCKD also result in favorable lipid profile changes. However, these beneficial effects can be limited by poor dietary adherence. Cultural, religious, and economic barriers pose unique challenges to achieving nutritional compliance with LCD and VLCKD. We review the various methods for assessing adherence in clinical studies and obstacles posed, as well as potential solutions to these challenges., Competing Interests: Dr William S Yancy Jr reports personal fees from dietdoctor.com. The authors report no other conflicts of interest in this work., (© 2022 Kumar et al.)

Background: Illuminating heterogeneity of treatment effect (HTE) within trials is important for identifying target populations for implementation., Objective: The aim of this study was to examine HTE in a trial of group medical visits (GMVs) for patients with type 2 diabetes and elevated body mass index., Research Design and Measures: Participants (n=263) were randomized to GMV-based medication management plus low carbohydrate diet-focused weight management (WM/GMV; n=127) or GMV-based medication management alone (GMV; n=136) for diabetes control. We used QUalitative INteraction Trees, a tree-based clustering method, to identify subgroups with greater improvement in hemoglobin A1c (HbA1c) and weight from either WM/GMV or GMV. Subgroup predictors included 32 baseline demographic, clinical, and psychosocial factors. Internal validation was conducted to estimate bias in the range of mean outcome differences between arms., Results: QUalitative INteraction Trees analyses indicated that for patients who had not previously attempted weight loss, WM/GMV resulted in better glycemic control than GMV (mean difference in HbA1c improvement=1.48%). For patients who had previously attempted weight loss and had lower cholesterol and blood urea nitrogen, GMV was better than WM/GMV (mean difference in HbA1c improvement=1.51%). No treatment-subgroup effects were identified for weight. Internal validation resulted in moderate corrections in mean HbA1c differences between arms; however, differences remained in the clinically significant range., Conclusion: This work represents a novel step toward targeting care approaches for patients to maximize benefit based on individual patient characteristics., Competing Interests: W.S.Y. is a scientific advisor for dietdoctor.com. M.L.M. owns Amgen stock due to his spouse’s employment. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The decades-long dietary experiment embodied in the Dietary Guidelines for Americans (DGA) focused on limiting fat, especially saturated fat, and higher carbohydrate intake has coincided with rapidly escalating epidemics of obesity and type 2 diabetes (T2D) that are contributing to the progression of cardiovascular disease (CVD) and other diet-related chronic diseases. Moreover, the lack of flexibility in the DGA as it pertains to low carbohydrate approaches does not align with the contemporary trend toward precision nutrition. We argue that personalizing the level of dietary carbohydrate should be a high priority based on evidence that Americans have a wide spectrum of metabolic variability in their tolerance to high carbohydrate loads. Obesity, metabolic syndrome, and T2D are conditions strongly associated with insulin resistance, a condition exacerbated by increased dietary carbohydrate and improved by restricting carbohydrate. Low-carbohydrate diets are grounded across the time-span of human evolution, have well-established biochemical principles, and are now supported by multiple clinical trials in humans that demonstrate consistent improvements in multiple established risk factors associated with insulin resistance and cardiovascular disease. The American Diabetes Association (ADA) recently recognized a low carbohydrate eating pattern as an effective approach for patients with diabetes. Despite this evidence base, low-carbohydrate diets are not reflected in the DGA. As the DGA Dietary Patterns have not been demonstrated to be universally effective in addressing the needs of many Americans and recognizing the lack of widely available treatments for obesity, metabolic syndrome, and T2D that are safe, effective, and sustainable, the argument for an alternative, low-carbohydrate Dietary Pattern is all the more compelling.

Abstract: Rosenberg, J, Hyde, PN, Yancy, WS, Ford, KM, and Champ, CE. Quantity of resistance exercise for breast cancer patients: does the dose match the objective? J Strength Cond Res 35(5): 1467-1476, 2021-There is currently a lack of consensus as to what defines exercise and resistance training in the cancer setting and whether current studies comply with exercise guidelines. This study aimed to quantify the available research studies using resistance training exercise interventions in the breast cancer setting for future clinical trial utilization. We systemically reviewed all available resistance exercise studies during and after breast cancer treatment in an attempt to quantify to the prescribed dose and whether regimens aligned with general exercise guidelines to improve functional mobility, body composition, and metabolic function. They were then compared with recommendations set forth by the national committees that create evidence-based exercise guidelines. Fifty studies met the initial criteria, with 35 meeting analysis criteria for evaluation. Fifteen studies evaluated an exercise regimen during cancer treatment, and 20 evaluated a regimen after treatment. The average adherence rates were 84% for all studies. Only 23 studies listed specific exercises used within the protocol. Most exercise regimens relied on open chain movements and machine exercises. Around half of studies met criteria to achieve hypertrophy, and 66% met American College of Sports Medicine exercise guidelines for cancer patients. A minority of breast cancer studies implementing a resistance training exercise regimen prescribed a regimen or specific dose that follows general exercise guidelines. This study highlights a potential deficiency in exercise programs designed for patients with breast cancer, and these findings should be considered in future study design., (Copyright © 2021 National Strength and Conditioning Association.)

Introduction: Long-term effects of behavioral weight loss maintenance interventions need to be assessed in order to understand their durability of effects. This can be evaluated with the use of weights recorded in the electronic medical record. The goal of this study was to use electronic health record (EHR)-recorded weight to examine outcomes 2 years beyond the completion of a trial in which participants were randomized to receive a weight maintenance intervention or usual care after required initial weight loss., Methods: Weights collected in the Veteran's Affairs national EHR were obtained for 2 years following trial completion. Outliers and implausible weights were identified and removed prior to analysis. Mixed-effects models with quadratic time were fit to estimate between-arm differences in weight change., Results: Model-estimated weight at trial completion was 109.7 kg for usual care and 106.8 kg for intervention, estimated difference of -2.9 kg (95% confidence interval [CI]: -8.8, 3.0; p  = 0.34). Two years later, estimated mean weight collected from ( n  = 211) participants with available EMR weights was 111.5 kg for usual care and 108.0 kg for intervention, estimated difference -3.4 kg (95% CI: -9.3, 2.4 kg; p  = 0.35)., Conclusions: While not statistically significant, weights from the EHR suggest the possibility of a clinically meaningful difference that should be confirmed by future adequately powered studies., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Purpose of Review: This study will provide a narrative review of the history of the clinical use of low-carbohydrate diets and give a practical example of how to implement a low-carbohydrate diet, with an emphasis on deprescribing medications., Recent Findings: Low-carbohydrate diets have been used since the late 19th century to treat obesity and type 2 diabetes mellitus (T2DM). Recently, clinical research has validated the use of low-carbohydrate diets for individuals affected by obesity and T2DM, and these diets are included in several national clinical guidelines. Because medications are commonly used to treat hypertension and T2DM, special consideration must be made to monitor and reduce these medications to avoid overmedication. Clinic visits and home monitoring of blood pressure and glucose levels are important tools to alert clinicians that a reduction in medication levels may be indicated., Summary: Low-carbohydrate diets have been utilized clinically for many years to treat obesity and T2DM and can be used alongside effective monitoring to safely deprescribe dispensable medications for these diseases.

Background: Behavioral interventions produce clinically significant weight reduction, with many participants regaining weight subsequently. Most interventions focus on an individual, but dietary and physical activity behaviors occur with, or are influenced by, domestic partners. According to interdependence theory, couples who approach behavior change as a problem to be tackled together versus independently are more likely to utilize communal coping processes to promote behavior change. We utilized interdependence theory to develop a partner-assisted intervention to increase long-term weight loss., Methods: Community-dwelling individuals (index participants) cohabitating with a partner with 1) overweight and at least one obesity-related comorbidity or 2) obesity are randomized to participate in a standard weight management program alone or with their partner. The weight management program involves biweekly, in-person, group sessions focusing on weight loss for six months, followed by three group sessions and nine telephone calls focusing on weight loss maintenance for twelve months. In the partner-assisted arm, partners participate in half of the group sessions and telephone calls. Couples receive training in principles of cognitive behavioral therapy for couples, including sharing thoughts and feelings and joint problem solving, to increase communal coping. The primary outcome is participant weight loss at 24 months, with caloric intake and moderate-intensity physical activity as secondary outcomes. Partner weight and caloric intake will also be analyzed. Mediation analyses will examine the role of interdependence variables and social support., Discussion: This trial will provide knowledge about effective ways to promote long-term weight loss and the role of interdependence constructs in weight loss. Clinical trials identifier: NCT03801174., (Published by Elsevier Inc.)

Low-carbohydrate diets have been advocated as an effective method for promoting weight loss in overweight and obese individuals and preventing and treating type 2 diabetes. This article reviews the differences between various low-carbohydrate eating plans and discusses the benefits and drawbacks of such a diet based on available evidence. It also offers practical pointers for clinicians., (© 2020 by the American Diabetes Association.)

Diabetes mellitus and obesity both contribute to chronic kidney disease (CKD) and diabetic kidney disease (DKD), and they can accelerate the loss of kidney function. Dietary intake can potentially have wide-reaching effects on the risk of CKD/DKD and their progression by reducing weight and blood pressure, improving glycemic control, reducing hyperfiltration, and modulating inflammation. Low-carbohydrate (LC) diets can reduce weight and improve glycemic control, but the relatively higher protein content also raises concern in CKD/DKD. Empiric evidence supporting the kidney-related benefits or risks of LC diets is needed to understand the balance of these potential harms and benefits for patients with DKD and is the subject of our review., (© 2019 New York Academy of Sciences.)

Purpose of Review: The purpose of this review is to summarize our current knowledge of factors that influence clinical decision making and management of type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) among South Asians (SA)., Recent Findings: ASCVD and T2DM in SAs have been examined in recent times. Pathophysiologic and genetic factors including the role of adiponectin, visceral adiposity, lower beta cell function, and psycho-social factors like sedentary lifestyle, poor adherence to medications, and carbohydrate dense meals play a role in early development and the high-risk presentation of both ASCVD and T2DM in SA. Recently, large population-based cohort studies have attempted to compare outcomes and interventions that can be translated to timely detection and targeted interventions in this high-risk group. SAs in the USA are more likely to be diagnosed with T2DM and ASCVD when compared to non-Hispanic whites, non-Hispanic Blacks, and Hispanic populations. The development of personalized ethnic risk assessment tools and better representation of SAs in prospective studies are essential to increasing our understanding and management of cardio-metabolic disease in SA living in the USA.

Importance: Traditionally, group medical visits (GMVs) for persons with diabetes improved glycemia by intensifying medications, which infrequently led to weight loss. Incorporating GMVs with intensive dietary change could enable weight loss and improve glycemia while decreasing medication intensity., Objective: To examine whether a program of GMVs combined with intensive weight management (WM) is noninferior to GMVs alone for change in glycated hemoglobin (HbA1c) level at 48 weeks (prespecified margin of 0.5%) and superior to GMVs alone for hypoglycemic events, diabetes medication intensity, and weight loss., Design, Setting, and Participants: This randomized clinical trial identified via the electronic medical record 2814 outpatients with type 2 diabetes, uncontrolled HbA1c, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 27 or higher from Veterans Affairs Medical Center clinics in Durham and Greenville, North Carolina. Between January 12, 2015, and May 30, 2017, 263 outpatients started the intervention., Interventions: Participants randomized to the GMV group (n = 136) received counseling about diabetes-related topics with medication optimization every 4 weeks for 16 weeks, then every 8 weeks (9 visits). Participants randomized to the WM/GMV group (n = 127) received low-carbohydrate diet counseling with baseline medication reduction and subsequent medication optimization every 2 weeks for 16 weeks followed by an abbreviated GMV intervention every 8 weeks (13 visits)., Main Outcomes and Measures: Outcomes included HbA1c level, hypoglycemic events, diabetes medication effect score, and weight at 48 weeks analyzed using hierarchical generalized mixed models to account for clustering within group sessions., Results: Among 263 participants (mean [SD] age, 60.7 [8.2] years; 235 [89.4%] men; 143 [54.4%] black), baseline HbA1c level was 9.1% (1.3%) and BMI was 35.3 (5.1). At 48 weeks, HbA1c level was improved in both study arms (8.2% in the WM/GMV arm and 8.3% in the GMV arm; mean difference, -0.1%; 95% CI, -0.5% to 0.2%; upper 95% CI, <0.5% threshold; P = .44). The WM/GMV arm had lower diabetes medication use (mean difference in medication effect score, -0.5; 95% CI, -0.6 to -0.3; P < .001) and greater weight loss (mean difference, -3.7 kg; 95% CI, -5.5 to -1.9 kg; P < .001) than did the GMV arm at 48 weeks and approximately 50% fewer hypoglycemic events (incidence rate ratio, 0.49; 95% CI, 0.27 to 0.71; P < .001) during the 48-week period., Conclusions and Relevance: In GMVs for diabetes, addition of WM using a low-carbohydrate diet was noninferior for lowering HbA1c levels compared with conventional medication management and showed advantages in other clinically important outcomes., Trial Registration: ClinicalTrials.gov identifier: NCT01973972.

Importance: Bariatric surgery has been associated with improvements in health in patients with severe obesity; however, it is unclear whether these health benefits translate into lower health care expenditures., Objective: To examine 10-year health care expenditures in a large, multisite retrospective cohort study of veterans with severe obesity who did and did not undergo bariatric surgery., Design, Setting, and Participants: A total of 9954 veterans with severe obesity between January 1, 2000, and September 30, 2011, were identified from veterans affairs (VA) electronic health records. Of those, 2498 veterans who underwent bariatric surgery were allocated to the surgery cohort. Sequential stratification was used to match each patient in the surgery cohort with up to 3 patients who had not undergone bariatric surgery but were of the same sex, race/ethnicity, diabetes status, and VA regional network and were closest in age, body mass index (calculated as weight in kilograms divided by height in meters squared), and comorbidities. A total of 7456 patients were identified and allocated to the nonsurgery (control) cohort. The VA health care expenditures among the surgery and nonsurgery cohorts were estimated using regression models. Data were analyzed from July to August 2018 and in April 2019., Interventions: The bariatric surgical procedures (n = 2498) included in this study were Roux-en-Y gastric bypass (1842 [73.7%]), sleeve gastrectomy (381 [15.3%]), adjustable gastric banding (249 [10.0%]), and other procedures (26 [1.0%])., Main Outcomes and Measures: The study measured total, outpatient, inpatient, and outpatient pharmacy expenditures from 3 years before surgery to 10 years after surgery, excluding expenditures associated with the initial bariatric surgical procedure., Results: Among 9954 veterans with severe obesity, 7387 (74.2%) were men; the mean (SD) age was 52.3 (8.8) years for the surgery cohort and 52.5 (8.7) years for the nonsurgery cohort. Mean total expenditures for the surgery cohort were $5093 (95% CI, $4811-$5391) at 7 to 12 months before surgery, which increased to $7448 (95% CI, $6989-$7936) at 6 months after surgery. Postsurgical expenditures decreased to $6692 (95% CI, $6197-$7226) at 5 years after surgery, followed by a gradual increase to $8495 (95% CI, $7609-$9484) at 10 years after surgery. Total expenditures were higher in the surgery cohort than in the nonsurgery cohort during the 3 years before surgery and in the first 2 years after surgery. The expenditures of the 2 cohorts converged 5 to 10 years after surgery. Outpatient pharmacy expenditures were significantly lower among the surgery cohort in all years of follow-up ($509 lower at 3 years before surgery and $461 lower at 7 to 12 months before surgery), but these cost reductions were offset by higher inpatient and outpatient (nonpharmacy) expenditures., Conclusions and Relevance: In this cohort study of 9954 predominantly older male veterans with severe obesity, total health care expenditures increased immediately after patients underwent bariatric surgery but converged with those of patients who had not undergone surgery at 10 years after surgery. This finding suggests that the value of bariatric surgery lies primarily in its associations with improvements in health and not in its potential to decrease health care costs.

Importance: Identifying effective strategies for treating obesity is a public health priority., Objective: To test an escalating lottery-based incentive tied to daily self-weighing for weight loss maintenance., Design, Setting, and Participants: This 2-phase, 2-arm randomized clinical trial enrolled participants aged 30 to 80 years with an initial body mass index (calculated as weight in kilograms divided by height in meters squared) of 30.0 to 45.0 who lost at least 5 kg during 4 to 6 months in a national online weight management program. Study investigators and outcomes assessors were blinded to participant groups. Data were collected and analyzed from May 23, 2016, through November 13, 2017, based on intention to treat., Interventions: All participants were advised to weigh themselves daily, with a goal of 6 or more days per week, and received text messaging feedback on their performance. Incentive group participants were eligible for a lottery-based incentive worth an expected value of $3.98 in week 1 that escalated by $0.43 each week they achieved their self-weighing goal during months 1 to 6 (phase 1), followed by no incentives during months 7 to 12 (phase 2)., Main Outcomes and Measures: The primary outcome was weight change at the end of phase 1. Secondary outcomes included weight change at the end of phase 2 and changes in self-reported physical activity and eating behaviors., Results: A total of 258 participants (128 in the incentive group and 130 in the control group) had a mean (SD) age of 48.0 (10.5) years and mean (SD) body mass index of 32.1 (3.9); 225 (87.2%) were women; 235 (91.1%) were white; and 102 (39.5%) had an annual income of at least $100 000. Weight measurement was transmitted by 250 participants (96.9%) at 6 months and 227 (88.0%) at 12 months. The percentage of weeks that incentive and control participants achieved a mean self-weighing of at least 6 times was 85.3% vs 75.8%, respectively (P = .002) in phase 1 and 37.7% vs 50.2%, respectively (P = .009) in phase 2. Mean weight changes at the end of phase 1 were -1.1 (95% CI, -2.1 to -0.1) kg in the incentive group and -1.9 (95% CI, -2.9 to -0.8) kg in the control group, with a mean difference of 0.7 (95% CI, -0.7 to 2.2) kg (P = .30 for comparison). At the end of phase 2, mean weight changes were 0.2 (95% CI, -1.2 to 1.7) kg in the incentive group and -0.6 (95% CI, -2.0 to 0.8) kg in the control group, with a mean difference of 0.8 (95% CI, -1.2 to 2.8) kg (P = .41 for comparison)., Conclusions and Relevance: Compared with an active control condition of weekly messages, escalating lottery-based incentives transiently increased rates of self-weighing but did not significantly enhance weight loss maintenance., Trial Registration: ClinicalTrials.gov identifier: NCT01900392.

Behavioral weight loss interventions are often delivered in groups. Group cohesion may enhance program attendance and, thereby, weight loss. In this secondary analysis, our goals were to: (1a) assess whether group cohesion measured early in a behavioral weight loss intervention predicts program attendance and weight loss outcomes and, if so, (1b) explore whether attendance mediates the link between group cohesion and weight loss; (2) characterize the association between change in group cohesion and weight loss throughout the intervention. Veterans (n = 324) initiated a 16-week, group-based behavioral weight loss program involving biweekly in-person group visits. In linear regression models, early group cohesion was unrelated to group attendance or weight loss. Although group cohesion significantly increased during the intervention, this change was not associated with weight loss. These findings are consistent with the limited literature; however, they are inconsistent with theoretical assertions and clinical observations of the influence of group factors on outcomes.

Introduction: Type 2 diabetes mellitus (T2DM) has reached epidemic proportions in the modern world. For individuals affected by obesity-related T2DM, clinical studies have shown that carbohydrate restriction and weight loss can improve hyperglycemia, obesity, and T2DM., Areas Covered: Reducing carbohydrate intake to a certain level, typically below 50 g per day, leads to increased ketogenesis in order to provide fuel for the body. Such low-carbohydrate, ketogenic diets were employed to treat obesity and diabetes in the 19 th and early 20 th centuries. Recent clinical research has reinvigorated the use of the ketogenic diet for individuals with obesity and diabetes. Although characterized by chronic hyperglycemia, the underlying cause of T2DM is hyperinsulinemia and insulin resistance, typically as a result of increased energy intake leading to obesity. The ketogenic diet substantially reduces the glycemic response that results from dietary carbohydrate as well as improves the underlying insulin resistance. This review combines a literature search of the published science and practical guidance based on clinical experience., Expert Commentary: While the current treatment of T2DM emphasizes drug treatment and a higher carbohydrate diet, the ketogenic diet is an effective alternative that relies less on medication, and may even be a preferable option when medications are not available.

Background: Evidence-based behavioral weight loss interventions are under-utilized. To inform efforts to increase uptake of these interventions, it is important to understand the perspectives of adults with obesity regarding barriers and facilitators of weight loss intervention initiation., Methods: We conducted a qualitative study in adults with obesity who had recently attempted weight loss either with assistance from an evidence-based behavioral intervention (intervention initiators) or without use of a formal intervention (intervention non-initiators). We recruited primary care patients, members of a commercial weight loss program, and members of a Veterans Affairs weight loss program. Intervention initiators and non-initiators were interviewed separately using a semi-structured interview guide that asked participants about barriers and facilitators of weight loss intervention initiation. Conversations were audio-recorded and transcribed. Data were analyzed with qualitative content analysis. Two researchers used open coding to generate the code book on a subset of transcripts and a single researcher coded remaining transcripts. Codes were combined into subthemes, which were combined in to higher order themes. Intervention initiators and non-initiators were compared., Results: We conducted three focus groups with participants who had initiated interventions (n = 26) and three focus groups (n = 24) and 8 individual interviews with participants who had not initiated interventions. Intervention initiators and non-initiators were, respectively, 65% and 37.5% white, 62% and 63% female, mean age of 55 and 54 years old, and mean BMI of 34 kg/m 2 . Three themes were identified. One theme was practical factors, with subthemes of reasonable cost and scheduling compatibility. A second theme was anticipated effectiveness of intervention, with subthemes of intervention content addressing individual needs; social aspects influencing effectiveness; and evaluating evidence of effectiveness. A third theme was anticipated pleasantness of intervention, with subthemes of social aspects influencing enjoyment; anticipated dietary and tracking prescriptions; and identity and self-reliance factors. Different perspectives were identified from intervention initiators and non-initiators., Conclusions: Strategies to engage individuals in evidence-based weight loss interventions can be developed using these results. Strategies could target individuals' perceived barriers and benefits to initiating interventions, or could focus on refining interventions to appeal to more individuals.

Objectives: To evaluate glycemic control among children and adults with type 1 diabetes mellitus (T1DM) who consume a very low-carbohydrate diet (VLCD)., Methods: We conducted an online survey of an international social media group for people with T1DM who follow a VLCD. Respondents included adults and parents of children with T1DM. We assessed current hemoglobin A1c (HbA1c) (primary measure), change in HbA1c after the self-reported beginning of the VLCD, total daily insulin dose, and adverse events. We obtained confirmatory data from diabetes care providers and medical records., Results: Of 316 respondents, 131 (42%) were parents of children with T1DM, and 57% were of female sex. Suggestive evidence of T1DM (based on a 3-tier scoring system in which researchers took into consideration age and weight at diagnosis, pancreatic autoimmunity, insulin requirement, and clinical presentation) was obtained for 273 (86%) respondents. The mean age at diagnosis was 16 ± 14 years, the duration of diabetes was 11 ± 13 years, and the time following a VLCD was 2.2 ± 3.9 years. Participants had a mean daily carbohydrate intake of 36 ± 15 g. Reported mean HbA1c was 5.67% ± 0.66%. Only 7 (2%) respondents reported diabetes-related hospitalizations in the past year, including 4 (1%) for ketoacidosis and 2 (1%) for hypoglycemia., Conclusions: Exceptional glycemic control of T1DM with low rates of adverse events was reported by a community of children and adults who consume a VLCD. The generalizability of these findings requires further studies, including high-quality randomized controlled trials., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Bernstein reported receiving royalties for books on the management of diabetes (which were used by members of the online social media group surveyed in this study). Dr Hallberg reported stock options and research support from Virta Health, a company that provides health care services for type 2 diabetes, and consulting fees from Atkins. Dr Rhodes is the site principal investigator in clinical trials for pediatric type 2 diabetes that are sponsored by Merck and AstraZeneca. Dr. Westman has ownership interest in companies using low-carbohydrate principles, and he receives royalties for books related to low-carbohydrate diets. Dr Ludwig reported receiving royalties from books on nutrition and obesity; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background/objective: Financial incentives can improve initial weight loss; we examined whether financial incentives can improve weight loss maintenance., Subjects/methods: Participants aged 30-80 years who lost at least 5 kg during the first 4-6 months in a nationally available commercial weight loss program were recruited via the internet into a three-arm randomized trial of two types of financial incentives versus active control during months 1-6 (Phase I) followed by passive monitoring during months 7-12 (Phase II). Interventions were daily self-weighing and text messaging feedback alone (control) or combined with a lottery-based incentive or a direct incentive. The primary outcome was weight change 6 months after initial weight loss. Secondary outcomes included weight change 12 months after initial weight loss (6 months after cessation of maintenance intervention), and self-reported physical activity and eating behaviors., Results: Of 191 participants randomized, the mean age was 49.0 (SD = 10.5) years and weight loss prior to randomization was 11.4 (4.7) kg; 92% were women and 89% were White. Mean weight changes during the next 6 months (Phase I) were: lottery -3.0 (5.8) kg; direct -2.8 (5.8) kg; and control -1.4 (5.8) kg (all pairwise comparisons p > 0.1). Weight changes through the end of 12 months post-weight loss (Phase II) were: lottery -1.8 (10.5) kg; direct -0.7 (10.7) kg; and control -0.3 (9.4) kg (all pairwise comparisons p > 0.1). The percentages of participants who maintained their weight loss (defined as gaining ≤1.36 kg) were: lottery 79%, direct 76%, and control 67% at 6 months and lottery 66%, direct 62%, and control 59% at 12 months (all pairwise comparisons p > 0.1). At 6 and 12 months after initial weight loss, changes in self-reported physical activity or eating behaviors did not differ across arms., Conclusions: Compared with the active control of daily texting based on daily home weighing, lottery-based and direct monetary incentives provided no additional benefit for weight loss maintenance.

Aim: To examine whether a low-carbohydrate, high-unsaturated/low-saturated fat diet (LC) improves glycaemic control and cardiovascular disease (CVD) risk factors in overweight and obese patients with type 2 diabetes (T2D)., Methods: A total of 115 adults with T2D (mean [SD]; BMI, 34.6 [4.3] kg/m 2 ; age, 58 [7] years; HbA1c, 7.3 [1.1]%) were randomized to 1 of 2 planned energy-matched, hypocaloric diets combined with aerobic/resistance exercise (1 hour, 3 days/week) for 2 years: LC: 14% energy as carbohydrate, 28% as protein, 58% as fat (<10% saturated fat); or low-fat, high-carbohydrate, low-glycaemic index diet (HC): 53% as CHO, 17% as protein, 30% as fat (<10% saturated fat). HbA1c, glycaemic variability (GV), anti-glycaemic medication effect score (MES, calculated based on the potency and dosage of diabetes medication), weight, body composition, CVD and renal risk markers were assessed before and after intervention., Results: A total of 61 (LC = 33, HC = 28) participants completed the study (trial registration: http://www.anzctr.org.au/, ANZCTR No. ACTRN12612000369820). Reductions in weight (estimated marginal mean [95% CI]; LC, -6.8 [-8.8,-4.7], HC, -6.6 [-8.8, -4.5] kg), body fat (LC, -4.3 [-6.2, -2.4], HC, -4.6 [-6.6, -2.7] kg), blood pressure (LC, -2.0 [-5.9, 1.8]/ -1.2 [-3.6, 1.2], HC, -3.2 [-7.3, 0.9]/ -2.0 [-4.5, 0.5] mmHg), HbA1c (LC, -0.6 [-0.9, -0.3], HC, -0.9 [-1.2, -0.5] %) and fasting glucose (LC, 0.3 [-0.4, 1.0], HC, -0.4 [-1.1, 0.4] mmol/L) were similar between groups (P ≥ 0.09). Compared to HC, the LC achieved greater reductions in diabetes medication use (MES; LC, -0.5 [-0.6, -0.3], HC, -0.2 [-0.4, -0.02] units; P = 0.03), GV (Continuous Overall Net Glycemic Action calculated every 1 hour (LC, -0.4 [-0.6, -0.3], HC, -0.1 [-0.1, 0.2] mmol/L; P = 0.001), and 4 hours (LC, -0.9 [-1.3, -0.6], HC, -0.2 [-0.6, 0.1] mmol/L; P = 0.02)); triglycerides (LC, -0.1 [-0.3, 0.2], HC, 0.1 [-0.2, 0.3] mmol/L; P = 0.001), and maintained HDL-C levels (LC, 0.02 [-0.05, 0.1], HC, -0.1 [-0.1, 0.01] mmol/L; P = 0.004), but had similar changes in LDL-C (LC, 0.2 [-0.1, 0.5], HC, 0.1 [-0.2, 0.4] mmol/L; P = 0.85), brachial artery flow mediated dilatation (LC, -0.5 [-1.5, 0.5], HC, -0.4 [-1.4, 0.7] %; P = 0.73), eGFR and albuminuria., Conclusions: Both diets achieved comparable weight loss and HbA1c reductions. The LC sustained greater reductions in diabetes medication requirements, and in improvements in diurnal blood glucose stability and blood lipid profile, with no adverse renal effects, suggesting greater optimization of T2D management., (© 2017 John Wiley & Sons Ltd.)

Background: Few studies have examined patterns of specific sleep problems among individuals with osteoarthritis (OA). The primary objective of this study was to examine prevalence of symptoms of insomnia and obstructive sleep apnea (OSA) among Veterans with OA. Secondary objectives were to assess proportions of individuals with insomnia and OSA symptoms who may have been undiagnosed and to examine Veterans' characteristics associated with insomnia and OSA symptoms., Methods: Veterans (n = 300) enrolled in a clinical trial completed the Insomnia Severity Index (ISI) and the Berlin Questionnaire (BQ) at baseline; proportions of participants with symptoms consistent with insomnia and OSA were calculated, using standard cut-offs for ISI and BQ. For Veterans with insomnia and OSA symptoms, electronic medical records were searched to identify whether there was a diagnosis code for these conditions. Multivariable linear (ISI) and logistic (BQ) regression models examined associations of the following characteristics with symptoms of insomnia and OSA: age, gender, race, self-reported general health, body mass index (BMI), diagnosis of post-traumatic stress disorder (PTSD), pain severity, depressive symptoms, number of joints with arthritis symptoms and opioid use., Results: Symptoms consistent with insomnia and OSA were found in 53 and 66% of this sample, respectively. Among participants screening positive for insomnia and OSA, diagnosis codes for these disorders were present in the electronic medical record for 22 and 51%, respectively. Characteristics associated with insomnia were lower age (β (SE) = - 0.09 (0.04), 95% confidence interval [CI] = - 0.16, - 0.02), having a PTSD diagnosis (β (SE) = 1.68 (0.73), CI = 0.25, 3.11), greater pain severity (β (SE) = 0.36 (0.09), CI = 0.17, 0.55), and greater depressive symptoms (β (SE) = 0.84 (0.07), CI = 0.70, 0.98). Characteristics associated with OSA were higher BMI (odds ratio [OR] = 1.13, CI = 1.06, 1.21), greater depressive symptoms (OR = 1.12, CI = 1.05, 1.20), and opioid use (OR = 0.51, CI = 0.26, 0.99)., Conclusions: Insomnia and OSA symptoms were very common in Veterans with OA, and a substantial proportion of individuals with symptoms may have been undiagnosed. Characteristics associated with insomnia and OSA symptoms were consistent with prior studies., Trial Registration: NCT01130740 .

The obesity epidemic has negative physical, psychological, and financial consequences. Despite the existence of effective behavioral weight loss interventions, many individuals do not achieve adequate weight loss, and most regain lost weight in the year following intervention. We report the rationale and design for a 2×2 factorial study that involves financial incentives for dietary self-monitoring (yes vs. no) and/or interim weight loss (yes vs. no). Outpatients with obesity participate in a 24-week, group-based weight loss intervention. All participants are asked to record their daily dietary and liquid intake on a smartphone application (app) and to weigh themselves daily at home on a study-provided cellular scale. An innovative information technology (IT) solution collates dietary data from the app and weight from the scale. Using these data, an algorithm classifies participants weekly according to whether they met their group's criteria to receive a cash reward ranging from $0 to $30 for dietary self-monitoring and/or interim weight loss. Notice of the reward is provided via text message, and credit is uploaded to a gift card. This pilot study will provide information on the feasibility of using this novel IT solution to provide variable-ratio financial incentives in real time via its effects on recruitment, intervention adherence, retention, and cost. This study will provide the foundation for a comprehensive, adequately-powered, randomized controlled trial to promote short-term weight loss and long-term weight maintenance. If efficacious, this approach could reduce the prevalence, adverse outcomes, and costs of obesity for millions of Americans. Clinicaltrials.gov registration: NCT02691260., (Published by Elsevier Inc.)

Purpose: To test the effects of employer subsidies on employee enrollment, attendance, and weight loss in a nationally available weight management program., Design: A randomized trial tested the impact of employer subsidy: 100%; 80%, 50%, and a hybrid 50% subsidy that could become a 100% subsidy by attaining attendance targets., Trial Registration: NCT01756066., Setting and Participants: Twenty three thousand twenty-three employees of 2 US companies., Measures: The primary outcome was the percentage of employees who enrolled in the weight management program. We also tested whether the subsidies were associated with differential attendance and weight loss over 12 months, as might be predicted by the expectation that they attract employees with differing degrees of motivation. Analysis and Results: Enrollment differed significantly by subsidy level ( P < .0001). The 100% subsidy produced the highest enrollment (7.7%), significantly higher than each of the lower subsidies (vs 80% subsidy: 6.2%, P = .002; vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Enrollment in the 80% subsidy group was significantly higher than both lower subsidy groups (vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Among enrollees, there were no differences among the 4 groups in attendance or weight loss., Conclusion: This pragmatic trial, conducted in a real-world workplace setting, suggests that higher rates of employer subsidization help individuals to enroll in weight loss programs, without a decrement in program effectiveness. Future research could explore the cost-effectiveness of such subsidies or alternative designs.

Background: Few evaluations of the Veterans Health Administration Motivating Overweight/Obese Veterans Everywhere (MOVE!) weight management program have assessed 6-month weight change or factors associated with weight change by gender., Materials and Methods: Analysis of administrative data from a national sample of veterans in the VA MOVE!, Results: A total of 62,882 participants were included, 14.6% were women. Compared with men, women were younger (49.6 years [standard deviation, SD, 10.8] vs. 59.3 years [SD, 9.8], p < 0.0001), less likely to be married (34.1% vs. 56.0%, p < 0.0001), and had higher rates of post-traumatic stress disorder (26.0% vs. 22.4%, p < 0.0001) and depression (49.3% vs. 32.9%, p < 0.001). The mean number of MOVE! visits attended by women was lower than men (5.6 [SD, 5.3] vs. 6.0 [SD, 5.9], p < 0.0001). Women, compared with men, reported lower rates of being able to rely on family or friends (35.7% vs. 40.8%, p < 0.0001). Observed mean percent change in weight for women was -1.5% (SD, 5.2) and for men was -1.9% (SD, 4.8, p < 0.0001). The odds of ≥5% weight loss were no different for women (body-mass index [BMI] >25 kg/m 2 ) compared with men (BMI >25 kg/m 2 ; odds ratio, 1.05 [95% confidence interval, 0.99-1.11; p = 0.13])., Conclusions: Women veterans lost less weight overall compared with men. There was no difference in the odds of achieving clinically significant weight loss by gender. The majority of women and men enrolled lost <5% weight despite being enrolled in a lifestyle intervention. Future studies should focus on identifying program- and participant-level barriers to weight loss.

Background: Rates of glycemic control remain suboptimal nationwide. Medication intensification for diabetes can have undesirable side effects (weight gain, hypoglycemia), which offset the benefits of glycemic control. A Shared Medical Appointment (SMA) intervention for diabetes that emphasizes weight management could improve glycemic outcomes and reduce weight while simultaneously lowering diabetes medication needs, resulting in less hypoglycemia and better quality of life. We describe the rationale and design for a study evaluating a novel SMA intervention for diabetes that primarily emphasizes low-carbohydrate diet-focused weight management., Methods: Jump Starting Shared Medical Appointments for Diabetes with Weight Management (Jump Start) is a randomized, controlled trial that is allocating overweight Veterans (body mass index≥27kg/m 2 ) with type 2 diabetes into two arms: 1) a traditional SMA group focusing on medication management and self-management counseling; or 2) an SMA group that combines low-carbohydrate diet-focused weight management (WM/SMA) with medication management. Hemoglobin A1c reduction at 48weeks is the primary outcome. Secondary outcomes include hypoglycemic events, diabetes medication use, weight, medication adherence, diabetes-related quality of life, and cost-effectiveness. We hypothesize that WM/SMA will be non-inferior to standard SMA for glycemic control, and will reduce hypoglycemia, diabetes medication use, and weight relative to standard SMA, while also improving quality of life and costs., Conclusions: Jump Start targets two common problems that are closely related but infrequently managed together: diabetes and obesity. By focusing on diet and weight loss as the primary means to control diabetes, this intervention may improve several meaningful patient-centered outcomes related to diabetes., (Copyright © 2017. Published by Elsevier Inc.)

Background: Weight regain after successful weight loss interventions is common., Objective: To establish the efficacy of a weight loss maintenance program compared with usual care in obese adults., Design: 2-group, parallel, randomized trial stratified by initial weight loss (<10 kg vs. ≥10 kg), conducted from 20 August 2012 to 18 December 2015. Outcome assessors were blinded to treatment assignment. (ClinicalTrials.gov: NCT01357551)., Setting: 3 primary care clinics at the Veterans Affairs Medical Center in Durham and Raleigh, North Carolina., Patients: Obese outpatients (body mass index ≥30 kg/m2) who lost 4 kg or more of body weight during a 16-week, group-based weight loss program., Intervention: The maintenance intervention, delivered primarily by telephone, addressed satisfaction with outcomes, relapse-prevention planning, self-monitoring, and social support. Usual care involved no contact except for study measurements., Measurements: Primary outcome was mean weight regain at week 56. Secondary outcomes included self-reported caloric intake, walking, and moderate physical activity., Results: Of 504 patients in the initial program, 222 lost at least 4 kg of body weight and were randomly assigned to maintenance (n = 110) or usual care (n = 112). Retention was 85%. Most patients were middle-aged white men. Mean weight loss during initiation was 7.2 kg (SD, 3.1); mean weight at randomization was 103.6 kg (SD, 20.4). Estimated mean weight regain was statistically significantly lower in the intervention (0.75 kg) than the usual care (2.36 kg) group (estimated mean difference, 1.60 kg [95% CI, 0.07 to 3.13 kg]; P = 0.040). No statistically significant differences in secondary outcomes were seen at 56 weeks. No adverse events directly attributable to the intervention were observed., Limitations: Results may not generalize to other settings or populations. Dietary intake and physical activity were self-reported. Duration was limited to 56 weeks., Conclusion: An intervention focused on maintenance-specific strategies and delivered in a resource-conserving way modestly slowed the rate of weight regain in obese adults., Primary Funding Source: Veterans Affairs Health Services Research and Development Service.

Background: A single-site study showed that a combined patient and provider intervention improved outcomes for patients with knee osteoarthritis, but it did not assess separate effects of the interventions., Objective: To examine whether patient-based, provider-based, and patient-provider interventions improve osteoarthritis outcomes., Design: Cluster randomized trial with assignment to patient, provider, and patient-provider interventions or usual care. (ClinicalTrials.gov: NCT01435109)., Setting: 10 Duke University Health System community-based primary care clinics., Participants: 537 outpatients with symptomatic hip or knee osteoarthritis., Intervention: The telephone-based patient intervention focused on weight management, physical activity, and cognitive behavioral pain management. The provider intervention involved electronic delivery of patient-specific osteoarthritis treatment recommendations to providers., Measurements: The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at 12 months. Secondary outcomes were objective physical function (Short Physical Performance Battery) and depressive symptoms (Patient Health Questionnaire). Linear mixed models assessed the difference in improvement among groups., Results: No difference was observed in WOMAC score changes from baseline to 12 months in the patient (-1.5 [95% CI, -5.1 to 2.0]; P = 0.40), provider (2.5 [CI, -0.9 to 5.9]; P = 0.152), or patient-provider (-0.7 [CI, -4.2 to 2.8]; P = 0.69) intervention groups compared with usual care. All groups had improvements in WOMAC scores at 12 months (range, -3.7 to -7.7). In addition, no differences were seen in objective physical function or depressive symptoms at 12 months in any of the intervention groups compared with usual care., Limitations: The study involved 1 health care network. Data on provider referrals were not collected., Conclusion: Contrary to a previous study of a combined patient and provider intervention for osteoarthritis in a Department of Veterans Affairs medical center, this study found no statistically significant improvements in the osteoarthritis intervention groups compared with usual care., Primary Funding Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Low enrollment in behavioral weight loss treatments limits their impact. We aimed to identify factors associated with treatment initiation. The participants were outpatients (n = 198) at Veterans Affairs (VA) healthcare facilities who were referred to a free VA-based behavioral weight loss treatment. Participants were assessed on psychosocial factors potentially relevant to treatment initiation. Subsequent treatment initiation was determined via medical record review. Study participants were 77 % male, 60 % African American, and 54 % initiated treatment. In multivariable analyses, treatment initiation was associated with being single, higher anxiety, and patients' perceptions that referring provider supported their weight autonomy. Endorsement of treatment barriers was not associated with treatment initiation. Treatments offering in-person sessions and mood management components were rated as more preferred. Initiation of behavioral weight loss treatments may increase if patients believe that providers respect their weight control autonomy and if healthcare organizations offer treatments that match patients' preferences.

Background Obesity continues to be a serious public health challenge. Rates are increasing worldwide, with nearly 70% of the US adults overweight or obese, leading to increased clinical and economic burden. While successful approaches for achieving weight loss have been identified, techniques for long-term maintenance of initial weight loss have largely been unsuccessful. Financial incentive interventions have been shown in several settings to be successful in motivating participants to adopt healthy behaviors. Purpose Keep It Off is a three-arm randomized controlled trial that compares the efficacy of a lottery-based incentive, traditional direct payment incentive, and control of daily feedback without any incentive for weight-loss maintenance. This design allows comparison of a traditional direct payment incentive with one based on behavioral economic principles that consider the underlying psychology of decision-making. Methods Participants were randomized in a 2:1 ratio for each active arm relative to control, with a targeted 188 participants in total. Eligible participants were those aged 30-80 who lost at least 11 lb (5 kg) during the first 4 months of participation in Weight Watchers, a national weight-loss program, with whom we partnered. The interventions lasted 6 months (Phase I); participants were followed for an additional 6 months without intervention (Phase II). The primary outcome is weight change from baseline to the end of Phase I, with the change at the end of Phase II a key secondary endpoint. Keep It Off is a pragmatic trial that recruited, consented, enrolled, and followed patients electronically. Participants were provided a wireless weight scale that electronically transmitted daily self-monitored weights. Weights were verified every 3 months at a Weight Watchers center local to the participant and electronically transmitted. Results Using the study web-based platform, we integrated recruitment, enrollment, and follow-up procedures into a digital platform that required little staff effort to implement and manage. We randomized 191 participants in less than 1 year. We describe the design of Keep It Off and implementation of enrollment. Lessons Learned We demonstrated that our pragmatic design was successful in rapid accrual of participants in a trial of interventions to maintain weight loss. Limitations Despite the nationwide reach of Weight Watchers, the generalizability of study findings may be limited by the characteristics of its members. The interventions under study are appropriate for settings where an entity, such as an employer or health insurance company, could offer them as a benefit. Conclusions Keep It Off was implemented and conducted with minimal staff effort. This study has the potential to identify a practical and effective weight-loss maintenance strategy.

Importance: Bariatric surgery induces significant weight loss for severely obese patients, but there is limited evidence of the durability of weight loss compared with nonsurgical matches and across bariatric procedures., Objectives: To examine 10-year weight change in a large, multisite, clinical cohort of veterans who underwent Roux-en-Y gastric bypass (RYGB) compared with nonsurgical matches and the 4-year weight change in veterans who underwent RYGB, adjustable gastric banding (AGB), or sleeve gastrectomy (SG)., Design, Setting, and Participants: In this cohort study, differences in weight change up to 10 years after surgery were estimated in retrospective cohorts of 1787 veterans who underwent RYGB from January 1, 2000, through September 30, 2011 (573 of 700 eligible [81.9%] with 10-year follow-up), and 5305 nonsurgical matches (1274 of 1889 eligible [67.4%] with 10-year follow-up) in mixed-effects models. Differences in weight change up to 4 years were compared among veterans undergoing RYGB (n = 1785), SG (n = 379), and AGB (n = 246). Data analysis was performed from September 9, 2014, to February 12, 2016., Exposures: Bariatric surgical procedures and usual care., Main Outcomes and Measures: Weight change up to 10 years after surgery through December 31, 2014., Results: The 1787 patients undergoing RYGB had a mean (SD) age of 52.1 (8.5) years and 5305 nonsurgical matches had a mean (SD) age of 52.2 (8.4) years. Patients undergoing RYGB and nonsurgical matches had a mean body mass index of 47.7 and 47.1, respectively, and were predominantly male (1306 [73.1%] and 3911 [73.7%], respectively). Patients undergoing RYGB lost 21% (95% CI, 11%-31%) more of their baseline weight at 10 years than nonsurgical matches. A total of 405 of 564 patients undergoing RYGB (71.8%) had more than 20% estimated weight loss, and 224 of 564 (39.7%) had more than 30% estimated weight loss at 10 years compared with 134 of 1247 (10.8%) and 48 of 1247 (3.9%), respectively, of nonsurgical matches. Only 19 of 564 patients undergoing RYGB (3.4%) regained weight back to within an estimated 5% of their baseline weight by 10 years. At 4 years, patients undergoing RYGB lost 27.5% (95% CI, 23.8%-31.2%) of their baseline weight, patients undergoing AGB lost 10.6% (95% CI, 0.6%-20.6%), and patients undergoing SG lost 17.8% (95% CI, 9.7%-25.9%). Patients undergoing RYGB lost 16.9% (95% CI, 6.2%-27.6%) more of their baseline weight than patients undergoing AGB and 9.7% (95% CI, 0.8%-18.6%) more than patients undergoing SG., Conclusions and Relevance: Patients in the Veterans Administration health care system lost substantially more weight than nonsurgical matches and sustained most of this weight loss in the long term. Roux-en-Y gastric bypass induced significantly greater weight loss among veterans than SG or AGB at 4 years. These results provide further evidence of the beneficial association between surgery and long-term weight loss that has been demonstrated in shorter-term studies of younger, predominantly female populations.

Unlabelled: Understanding associations between food preferences and weight loss during various effective diets could inform efforts to personalize dietary recommendations and provide insight into weight loss mechanisms. We conducted a secondary analysis of data from a clinical trial in which participants were randomized to either a 'choice' arm, in which they were allowed to select between a low-fat diet (n = 44) or low-carbohydrate diet (n = 61), or to a 'no choice' arm, in which they were randomly assigned to a low-fat diet (n = 49) or low-carbohydrate diet (n = 53). All participants were provided 48 weeks of lifestyle counseling. Food preferences were measured at baseline and every 12 weeks thereafter with the Geiselman Food Preference Questionnaire. Participants were 73% male and 51% African American, with a mean age of 55. Baseline food preferences, including congruency of food preferences with diet, were not associated with weight outcomes. In the low-fat diet group, no associations were found between changes in food preferences and weight over time. In the low-carbohydrate diet group, increased preference for low-carbohydrate diet congruent foods from baseline to 12 weeks was associated with weight loss from 12 to 24 weeks. Additionally, weight loss from baseline to 12 weeks was associated with increased preference for low-carbohydrate diet congruent foods from 12 to 24 weeks. Results suggest that basing selection of low-carbohydrate diet or low-fat diet on food preferences is unlikely to influence weight loss. Congruency of food preferences and weight loss may influence each other early during a low-carbohydrate diet but not low-fat diet, possibly due to different features of these diets., Clinical Trial Registry: NCT01152359., (Copyright © 2016 Elsevier Ltd. All rights reserved.)